Constipation refers to conditions where the number of bowel movements and the amount of stools decrease so much that the process of defecation involves pains or difficulties. On account of changes in eating habit, insufficient exercise, a time-bound and stressful social life, and the increasing population of the elderly, the frequency of constipation is presumably increasing.
Under normal conditions, food taken into the mouth is digested and absorbed, leaving undigested waste material as the bowel contents, which are then forwarded from the small to the large intestine. In the large intestine, the waste material solidifies as water is absorbed and in the process of its peristaltic movement toward the anus, it arrives at the sigmoid colon, where it is stored as stools. When the stools are propelled into the rectum by a contracting motion called mass peristalsis, the walls of the rectum stretch, signaling a stimulation that is conducted to the defecatory center in the spinal cord and a defecatory reflex takes place, causing the anal sphincter muscles to relax and the rectum to contract. Simultaneously, the cerebrum recognizes the urgency to pass stools and the abdominal pressure is increased voluntarily to initiate defecation. Components of constipation reportedly include decreased autonomic nerve, motility or defecatory reflex functions in the lower digestive tract, excessive water absorption in the intestinal tract, decreased secretion of intestinal juice, etc.
Major known cases of constipation include, for example, functional constipation, organic constipation, symptomatic constipation, and drug-induced constipation. Functional constipation is known to include, for example, transient simple constipation, atonic constipation due to decreased peristalsis of the large intestine, spasmodic constipation due to hypertonia of the colon mediated by the autonomic nerves, and rectal constipation due to weak defecatory reflex upon the arrival of stools in the rectum. Organic constipation is caused by obstruction or constriction of the intestinal tract due to underlying diseases in or around the intestinal tract. Symptomatic constipation is part of the symptoms of underlying diseases such as metabolic, endocrine, nerve, and myopathic diseases. Medicaments that are known to cause drug-induced constipation include psychotropic or antidepressant agents having an anti-cholinergic action, narcotics such as morphine, and vinca alkaloids as anticancer agents.
Constipation also occurs as an abnormal bowel movement in irritable bowel syndrome that involves abdominal discomfort or pain which lightens or disappears upon defecation. The elderly often complain of constipation associated with physiological changes due to the aging intestinal tract. Constipation is more common in women than in men because, for one thing, they have their own physical characteristic features such as weak abdominal muscles and, for another, they are subject to hormonal actions during the menstrual cycle. Pregnant women, too, complain of constipation due to hormonal actions and various other effects including compression of the intestinal tract, decreased motility of the diaphragm, and weakened abdominal muscles. Constipation also occurs as a somatic symptom of mental diseases such as depression and anxiety neurosis (Non-Patent Documents 1 and 2).
Medicaments used for constipation include: osmotic laxatives classified to be salt laxatives such as magnesium oxide or saccharide laxatives such as D-sorbitol; bulk-forming laxatives such as polycarbophil calcium; stimulant laxatives such as sennosides; and infiltrating laxatives such as dioctyl sodium sulfosuccinate. Also used are 5-hydroxytryptamine 4 (5-HT4) receptor agonists such as prucalopride, and type 2 chloride channel (ClC-2) agonists such as lubiprostone. Glycerin is one of the medicaments used as enemas.
Medical therapy of constipation starts with the use of salt or bulk-forming laxatives. The salt laxative magnesium oxide requires precautions to be taken against hypermagnesemia, particularly when they are used in the elderly or in patients with renal disorder. The bulk-forming laxative polycarbophil calcium is mild in action, taking time for the efficacy to develop. If these medicines prove inefficacious, stimulant laxatives are attempted. Stimulant laxatives act on the nerve plexus in the large intestinal tract to enhance peristalsis but upon prolonged use, they become addictive, causing atrophy of the nerve plexus to exacerbate the relaxation of the large intestine. The use of stimulant laxatives is limited to the smallest possible amount and the shortest possible period. Therefore, a therapeutic for constipation that is safer and more efficacious with less side effects which, although being mild in action, can rapidly develop its efficacy is expected to benefit many patients. As a further problem, stimulant laxatives have a mucosa irritating action, so if dissolved in the stomach or degraded with gastric acid, the mucosa of the stomach is irritated causing various side effects such as severe stomach pain, nausea, and vomiting; it is therefore recommended that stimulant laxatives be used as suppository. Hence, it is desired that even upon oral administration which is convenient and the most desirable, medicaments are preferably free of the side effect issue and that the active ingredient remains chemically stable and unaffected by metabolism as it passes through the strongly acidic stomach and then through the neutral bowels until it exhibits its efficacy in the target site bowel.
Now, sodium-dependent glucose cotransporter 1 (SGLT1) is a sodium cotransporter that is mainly found in epithelial cells in the small intestine and which is responsible for the absorption of glucose and galactose which result from the digestion of carbohydrates contained in meals. Since compounds that inhibit the SGLT1 existing in the small intestine suppress the absorption of saccharides, they are considered to be useful as hypoglycemic drugs, therapeutics for diabetes mellitus or as therapeutics for obesity, and efforts are being made to develop such pharmaceuticals. Compounds so far reported to be capable of suppressing SGLT1 include DSP-3235 (KGA-2727 or GSK1614235) (Patent Document 1), SAR474832 (Non-Patent Document 3), and LX4211 (Patent Document 2), as well as several other compounds (Patent Documents 3 and 4). However, none of these SGLT1 inhibiting compounds are known to be effective in preventing or treating constipation.